Jones et al. Hereditary Cancer in Clinical Practice 2013, 11:19
http://www.hccpjournal.eom/content/1 1/1/19
HEREDITARY CANCER
IN CLINICAL PRACTICE
RESEARCH Open Access
The impact of genetic variants in
inflammatory-related genes on prostate cancer
risk among men of African Descent: a case control
study
Dominique Z Jones 1 , Camille Ragin 2 , Nayla C Kidd 1 , Rafael E Flores-Obando 3 , Maria Jackson 4 ,
Norma McFarlane-Anderson 5 , Marshall Tulloch-Reid 6 , Kevin S Kimbro 7 and LaCreis R Kidd 1 *
Abstract
Purpose: Although case-control studies have evaluated the role of variant inflammatory-related loci in prostate
cancer, their impact is virtually unknown among men of African descent. To address this, we evaluated the impact
of inflammatory cytokine single nucleotide polymorphisms (SNPs) on prostate cancer risk for men of African
descent.
Methods: Forty-four SNPs in inflammatory cytokine-associated genes were evaluated among 814 African-American
and Jamaican men (279 prostate cancer cases and 535 controls) using lllumina's Golden gate genotyping system.
Individual SNP effects were evaluated using logistic regression analysis.
Results: Four SNPs were modestly associated with prostate cancer after adjusting for age. In the total population,
inheritance of the IL1R2 rsl 1 886877 AA, 1L8RB rsl 1 574752 AA, TNF rs1 800629 GA + AA, and TNF rs673 GA genotypes
modestly increased prostate cancer risk by 1.45 to 1 1.7-fold relative to the referent genotype. Among U.S. men,
age-adjusted dominant, recessive and additive genetic models for the IL1R2 rsl 1886877 locus were linked to an
increase in prostate cancer susceptibility. However, these main effects did not persist after adjusting for multiple
hypothesis testing.
Conclusion: Our preliminary data does not strongly support the hypothesis that inflammatory-related sequence
variants influence prostate cancer risk among men of African descent. However, further evaluation is needed to
assess whether other variant inflammatory-related genes may contribute to prostate cancer risk and disease
progression in larger and ethnically diverse multi-center studies.
Keywords: Prostate cancer, Inflammatory-related sequence variants, Single nucleotide polymorphisms
Introduction
Chronic inflammation is thought to predispose an individual
to cancer development [1]. This relationship is supported
by a number of studies involving inflammatory bowel
disease, colon cancer, hepatitis, liver cancer, pancreatitis, and
pancreatic cancer [2-6]. Through several lines of evidence
from epidemiological, histopathological, animal, genetic
and molecular pathological studies, chronic inflammation
* Correspondence: rkidd01@louisville.edu
'Department of Pharmacology & Toxicology, University of Louisville,
Louisville, KY, USA
Full list of author information is available at the end of the article
is also thought to play a major role in prostate cancer
development [2,3]. For example, prostatic infections have
been implicated in prostate cancer either through direct
or indirect promotion of the inflammatory process [1-3].
In addition, the use of non-steroidal anti-inflammatory
drugs (NSAIDS) and other anti-inflammatory agents have
been shown to reduce prostate cancer risk [4].
The production of cytokines can be influenced by single
nucleotide polymorphisms (SNPs) detected within pro- and
anti-inflammatory genes. Genetic variations in cytokine
related genes may lead to alterations in the spectrum of
cytokines expressed in an inflammatory environment or
© 201 3 Jones et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
BlOlVlGCl C^ntrs! Commons Attribution License (http//creativecomn ons.org/lii :nsi 1 hich perm ts unrestricted use, distribution, and
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Jones et al. Hereditary Cancer in Clinical Practice 2013, 11:19
http://www.hccpjournal.eom/content/1 1/1/19
Page 2 of 1 1
level of antitumor response [5]. Epidemiological studies
have reported on the relationship between prostate cancer
susceptibility and genes involved in the cytokine-cytokine
receptor signaling pathway, such as interleukins and their
receptors, ribonuclease L (RNASEL) and tumor necrosis
factor (TNF) [6-13]. While men of African Descent suf-
fer disproportionately from this disease [2,3,14,15], there is
limited information about the positive link between variant
cytokine genes and prostate cancer development in this
population [16,17]. Therefore, additional studies are
needed to investigate the role of inflammatory-related SNPs
in the development of prostate cancer among individuals of
African Descent.
The current study evaluated the impact of 44 inflamma-
tory-related sequence variants in relation to prostate cancer
risk among men of African Descent from the U.S. and
Jamaica. Findings from our study will help to fill in the
gaps in information pertinent to prostate cancer among
men of African Descent.
Materials and methods
Study population
Our study population, 279 cases and 535 controls, was
comprised of two independent case-control study sets.
These studies include the Prostate Cancer Clinical Out-
come Study (PC 2 OS) at the University of Louisville and
the Prostate Cancer Study in Jamaica at the University
of the West Indies, Mona Campus. For both study sets,
all incident prostate cancer cases were histologically
confirmed and the controls were assigned based on normal
PSA levels, and normal DREs/biopsies. Descriptions of each
contributing study have been previously described [18,19].
Briefly, the PC 2 OS study included 170 incident pros-
tate cancer cases and 433 controls recruited between
2001-2005 through the Howard University Hospital (HUH)
Division of Urology or related prostate cancer screening
programs. Enrolled participants were men of African des-
cent from the Washington, D.C. and Columbia, S.C. areas.
The racial subgroups included self-reported African
Americans, East African Americans, West African Americans,
and Caribbean Americans. The Prostate Cancer Study
in Jamaica included consecutively enrolled 109 incident
prostate cancer cases and 102 controls recruited from
2005-2007 through the Urology clinic at the University
Hospital of the West Indies in Kingston Jamaica.
Criteria for inflammatory gene and SNP selection
Inflammatory-associated genes and SNPs were selected
using one or more of the following criteria: (1) empirical
evidence that supports a relationship between the SNP/
gene and cancer or inflammatory/immune response related
diseases; (2) commonly studied loci; (3) marked disparities
in genotype frequency comparing men of African Descent
to their Caucasian counterparts (i.e., ±10% change); (4)
evidence demonstrating a link with alterations in mRNA
expression/stability or protein expression/structure or
function using in silico tools such as SNPinfo (http://
snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm) or published
reports; and (5) a minor allele frequency >5% reported in
the National Center for Biotechnology Information
(NCBI) Entrez SNP, (http://www.ncbi.nlm.nih.gov/snp).
According to NCBI, the selected SNPs had an average
minor allele frequency of 22%. However, the IL1RN
rs315951 SNP had an allele frequency of 2.1%. This rare
non-synonymous sequence variant was included in the
analysis to explore whether a rare SNP would lead to
substantial gains in effect sizes (i.e., 2-3 fold increases
in risk) and contribute to the missing genetic heritability
[20,21].
Genetic analysis of variant inflammatory-associated SNPs
Allelic discrimination of 44 inflammatory-associated se-
quence variants was performed using a custom Illumina
GoldenGate Genotyping assay with VeraCode Technology
and BeadXpress reader, according to the manufacturer's
instructions [22].
Statistical analysis
Evaluation of the relationship between variant inflammatory
associated alleles and prostate cancer risk was performed
using univariate and multivariate analyses. The chi-square
test of heterogeneity was used to assess for significant dif-
ferences in the distribution of homozygous major, hetero-
zygous, or homozygous minor genotypes between prostate
cancer cases and controls. Evaluation of the relationship
between prostate cancer risk and selected polymorphic
genes, expressed as odds ratios (ORs) and corresponding
95% confidence intervals (CIs), were estimated using
unconditional multivariate LR models adjusted for age. The
major or common genotype was used as the reference
category for each LR model. Statistical significance was
assessed using a Bonferroni Correction (a = 0.05/44
SNPs) cut-off of 0.001, in order to adjust for multiple
comparisons. All statistical analyses were performed using
SAS 9.3 (SAS Institute Inc., Cary, NC) and SNP Variation
Software 7.0 (Golden Helix, Bozeman, MT).
Statistical power
Based on our sample size for the total population, U.S.
and Jamaican men, we had >80% power to detect
SNPs with odds ratios (ORs) of >1.4, >1.6, >1.8, re-
spectively, for a co-dominant genetic model with 1
degree of freedom (df), a minor allele frequency of at
least 22% and disease prevalence of 0.74%. Analyses
were performed using Power for Genetic Association
Version 2 Software [23].
Jones et al. Hereditary Cancer in Clinical Practice 2013, 11:19
http://www.hccpjournal.eom/content/1 1/1/19
Page 3 of 1 1
Results
Prevalence of inflammatory-associated sequence variants
among men of African Descent
Inheritance of variant inflammatory-related loci was fairly
common among African- American men in the current
study. Specifically, the minor allele frequencies of the
44 sequence variants ranged from approximately 2.6%
to 48%, as depicted in Table 1. Notably, the observed
genotype frequency distribution among controls did not
significantly deviate from expected counts according to
the Hardy Weinberg equilibrium. With the exception of
four loci {IL1RN rs4251961, IL10RB rs999788, IL10RB
rs283416, and ILR1 rs3917225), the observed genotype
frequencies in the current study corroborated with values
for individuals of African-American/African ancestry
reported in the NCBI's SNP entrez (P = 0.063-1.000), as
shown in Table 1.
Relationship between inflammatory sequence variants
and prostate cancer risk
Seven out of 44 sequence variants detected in inflamma-
tory-related genes were modestly associated with prostate
cancer risk among 814 men of African Descent (279
cases and 535 controls), as summarized in Table 2. For
age-adjusted risk models, elevations in prostate cancer
susceptibility were observed among carriers of IL1R2
rsll88687 7AA (OR = 1.92; 95%CI= 1.11, 3.32), IL8RB
rsll574752 GA + AA (OR = 38.40; 95%CI = 3.86, 382.8),
TNF rsl800629 GA + AA (OR = 1.53; 95%CI = 1.06, 2.20),
and TNF rs673 GA (OR = 1.50; 95%CI = 1.04, 2.16) geno-
types with risk estimates ranging from 1.50-38.4. The
IL1R2 rsl 1886877 marker was the only genetic susceptibil-
ity factor significant under the additive genetic model
(P-trend = 0.010), indicative of a significant dose-response
effect in relation to the number of inherited minor alleles.
The aforementioned markers were not classified as im-
portant prostate cancer risk indicators after adjusting for
multiple comparisons bias using the Bonferroni correc-
tion, with a significance cut-off of <0.001.
Upon stratification by sub-population, modestly signifi-
cant prostate cancer biomarkers varied by racial/ethnic
group in the age adjusted risk models. Possession of the
RNASEL rsl213524 AG genotype was associated with a
2.17-fold increase in the risk of developing prostate cancer
(OR = 2.10; 95%CI = 1.04, 4.24) among Jamaican men, as
detailed in Table 3. However, this locus was not significant
in the dominant, recessive or additive genetic models.
Similar to the total population, inheritance of sequence
variants in IL1R2, IL10RA and TNF among U.S. men were
linked with a significant increase in prostate cancer risk.
Among U.S. men, two inflammatory-related sequence var-
iants, [IL1R2 rsl 1886877 (GA, GA + AA, AA) and IL10RA
rs4252243 AA], were associated with a 1.82-2.49-fold in-
crease in prostate cancer risk. Out of these 2 markers, the
IL1R2 rsl 1886877 locus was significant for the dominant
(OR = 2.75; 95%CI= 1.38, 5.50), co-dominant (OR = 1.82;
95%CI=1.14, 2.88), recessive (OR = 2.05; 95%CI=1.10,
3.80), and additive (P-trend value = 0.002) genetic models.
None of the aforementioned markers survived correction
for multiple hypotheses testing. Moreover, the IL10RA
rs4252243 SNP was only significantly related to prostate
cancer risk under the recessive genetic model (OR = 2.49;
95%CI = 1.08, 5.72).
Discussion
Chronic inflammation has been associated with tumor
development and metastasis. Inflammatory response is
regulated through a complex network of cytokines, cyto-
kine receptors and downstream targets that synergistically
regulate innate/humoral immune and inflammatory pro-
cesses. Recent molecular and genetic epidemiology studies
have demonstrated that chronic inflammation and suscep-
tibilities in inflammatory-associated genes are related to
the development of several cancers, including lymphoma,
and gastric and prostate cancer [6,16,24-26]. However,
to our knowledge, there are few published reports on
the impact of variant cytokine-related genes in relation to
prostate cancer among men of African Descent. There-
fore, the current study evaluated the individual effects of
44 inflammatory associated sequence variants on prostate
cancer risk among 279 cases and 535 disease-free men of
African Descent from the U.S and Jamaica. Our findings
revealed a modest increase in prostate cancer risk for un-
adjusted and adjusted logistic regression models for IL1R2
rsl 1886877 among men of African Descent. The additive,
dominant and recessive genetic models of this variant
were significant even after adjusting for age. However, this
relationship did not survive after accounting for multiple
comparisons bias.
IL1R2 rsll886877 is about 2415 base pairs from the
transcription start site, which suggest it may have a high
likelihood of regulating IL1R2 gene expression. Currendy,
there are no published reports on the relationship between
IL1R2 rsl 1886877 and prostate cancer for any population.
Although there is no evidence of the impact of this
sequence variant on prostate cancer risk among European
and African American men, the relationship between the
IL1R2 gene expression and prostate cancer has been dem-
onstrated through published reports [27-29]. Leshem and
colleagues (2011) found that the promoter region oiILlR2
possesses putative binding motifs for the TMPRSS2/ERG
fusion gene, which is highly expressed in aggressive pros-
tate cancer [27]. When the expression of IL1R2 was
knocked down using small interfering RNAs, it resulted
in the reduction of ZEB2 mRNA expression in hTERT/
shp53/CyclinD-CDK4 overexpressing cells exposed to
TMPRSS2/ERG [25]. TMPRSS2/ERG fusion gene indir-
ectly up-regulates ZEB2, a facilitator of the epithelial to
Table 1 Functional consequence and prevalence of inflammatory-associated sequence variants
dbSNPID Gene Location NCBI NCBI NCBI NCBI NCBI Current study Current
functional nucleotide minor allele major/major major/minor minor/minor nucleotide study MAF
consequence change frequency genotype genotype genotype change n(%) for
(major > (MAF) for n (%) for n (%) for n (%) for (major > African-
minor allelef African- African- African- African- minor allele) Americans
Americans Americans Americans Americans
Current
study
major/major
genotype
n (%) for
African-
Americans
Current
study
major/minor
genotype
n (%) for
African-
Americans
Current
study
minor/minor
genotype
n (%) for
African-
Americans
Overall x 2
P-value
comparing
genotypes from
individuals of
African Descent
as reported in
NCBI versus the
current study™
rs1058867 T
rsl 071 676*
rs1 11 23902*
rs 1126579*
rs 1143627*
rs 1143634*
rsl 1574752*
rs1 1886877
rsl 21 35247*
rsl 2328606*
rsl 304037*
rs16944*
rs17561*
rsl 799964*
rsl 800587*
rsl 800629*
rsl 800871*
L10RB
L1B
L1R2
L8RB
L1B
L1B
L8RB
L1R2
RNASEL
L1R2
L1A
L1B
L1A
TNF
ILIA
TNF
IL10
UTR'3
miRNA
UTR'3
miRNA
Intron 1
UTR'3
miRNA
Near gene 5'
TFBS
Exon 4
Splicing
UTR'3
miRNA
Intron 1
UTR'3
TFBS, miRNA
Near gene 5'
TFBS
UTR'3
miRNA
Near gene 5'
TFBS
Exon 4
Splicing,
nsSNP,
benign
Near gene 5'
TFBS
UTR'5
TFBS, Splicing
Near gene 5'
TFBS
Near gene 5'
TFBS
G > A
G>C
A>C
C>T
C>T
C>T
G > A
T>C
C>T
A > G
A > G
G >T
T>C
C>T
G > A
C>T
A = 37.9
C= 14.6
C = 31.8
T=14.5
T = 37.5
T= 12.9
A = 1 0.4
C= 16.3
T=11.2
G = 39.6
G = 39.0
T= 15.3
C= 12.9
T = 39.1
A = 13.7
T = 36.3
26 (42.0)
1 9 (79.2)
10 (45.5)
46 (74.2)
1 2 (50.0)
47 (75.8)
19 (79.2)
33 (67.3)
38 (77.6)
8 (33.3)
18 (30.5)
44 (71.0)
46 (74.2)
9 (39.1)
46 (74.2)
28 (45.2)
25 (40.3)
3 (12.5)
10 (45.5)
14 (22.6)
6 (25.0)
14 (22.6)
5 (20.8)
16 (32.7)
11 (22.4)
1 3 (54.2)
36 (61.0)
1 7 (27.4)
16 (25.8)
10 (43.5)
1 5 (24.2)
23 (37.1)
11 (17.7)
2 (8.3)
2 (9.10)
2 (3.20)
6 (25.0)
1 (1.60)
0(0.00)
0 (0.00)
0 (0.00)
3 (12.5)
5 (8.50)
1 (1.60)
0 (0.00)
4 (17.4)
1 (1.60)
11 (17.7)
G > A
G>C
A>C
G>A +
G>A +
G>A +
G > A
G > A
A>G +
G> A +
A > G
A > G
C>A +
A>G t
G>A +
G > A
G> A +
A = 33.9
C=16.1
C = 30.7
A = 13.8
A = 39.6
A = 15.5
A = 9.40
A = 35.8
G= 17.9
A = 13.5
G = 41 .1
G = 45.1
A = 18.6
239 (44.6)
378 (70.7)
258 (48.2)
402 (75.1)
1 94 (36.3)
381 (71.2)
435 (81.3)
211 (39.4)
368 (68.8)
405 (75.7)
191 (35.7)
1 56 (29.2)
358 (66.9)
229 (42.9)
142 (26.5)
225 (42.1)
118 (22.1)
256 (48.2)
142 (26.5)
99 (18.5)
265 (49.5)
142 (26.5)
116 (21.7)
248 (46.4)
275 (51.4)
1 55 (29.0)
67 (12.5)
1 5 (2.80)
52 (9.70)
1 5 (2.80)
83 (15.5)
1 2 (2.3)
1 (0.20)
59 (11.1)
25 (4.70)
14 (2.60)
96 (17.9)
1 04 (1 9.4)
22 (4.10)
G= 16.5 374 (69.9) 145(27.1) 16 (3.00)
A = 4 1 .8 1 83 (34.2) 25 7 (48.0) 95 ( 1 7.8)
A = 16.9
153(28.6) 14 (2.60)
A = 40.7 188 (35.0) 258(48.0) 89 (17.0)
0.514
0.106
0.949
0.886
0.063
0.833
0.798
0.226
0.798
0.760
0.108
0.698
0.492
0.885
0.752
0.219
Table 1 Functional consequence and prevalence of inflammatory-associated sequence variants (Continued)
Near gene 5' A>C
TFBS
Near gene 5' G > A
TFBS
Near gene 5' A > G
TFBS
rs2192752* IL1R1 Near gene 5' A>C
TFBS
rs1 800872" IL10
rs 1800893* IL10
rs 1800896* IL10
rs2227532* IL8
rs2227538* IL8
rs2227545* IL8
Near gene 5' T>C
TFBS
UTR'5 C>T
TFBS, Splicing
UTR'3 A > C
miRNA
rs2229113* IL10RA Exon 7
nsSNP,
probably
damaging
rs2834167* IL10RB Exon 2
Splicing,
nsSNP,
benign
rs2856836* ILIA UTR'3
miRNA
rs31 35932* IL10RA Exon 5
Splicing,
nsSNP,
benign
rs31595r
IL1RN UTR'3
miRNA
G > A
A > G
T>C
A > G
C>G
T>C
rs3738579* RNASEL UTR'5
TFBS, Splicing
rs3917225* IL1R1 Near gene 5' A > G
TFBS
rs4073*
IL8
Near gene 5' A>T
TFBS
rs4141134" IL1R2 Near gene 5' T>C
rs4251961* IL1RN Near gene 5' T>C
TFBS
rs4252243* IL10RA Near gene 5' C>T
TFBS
A = 50.0
C = 50.0
A = 37.1
G = 40.5
C = 4.80
C = 9.70
T= 17.7
C = 8.70
A = 20.5
C = 1 7.4
G = 2.10
G = 47.9
C = 1 6.7
G = 12.3
T=26.6
C = 1 1 .2
C = 20.2
T=32.5
5 (21.7)
22 (35.5)
7 (33.3)
56 (90.3)
50 (80.6)
41 (66.1)
1 9 (82.6)
14 (63.7)
1 6 (69.6)
23 (95.8)
8 (33.3)
14 (66.7)
49 (80.3)
34 (54.8)
39 (79.6)
37 (59.7)
9 (45.0)
13 (56.6)
34 (54.8)
1 1 (52.4)
6 (9.70)
12 (19.4)
20 (32.3)
4 (17.4)
7 (31.8)
G = 16.9 44(71.0) 15(24.2)
6 (26.1)
1 (4.20)
9 (37.5)
7 (33.3)
9 (14.8)
23 (37.1)
9 (18.4)
25 (40.3)
9 (45.0)
5 (21.7)
6 (9.70)
3 (14.3)
0 (0.00)
0 (0.00)
1 (1.60)
0 (0.00)
1 (4.50)
3 (4.80)
1 (4.30)
0 (0.00)
7 (29.2)
0 (0.00)
3 (4.90)
5 (8.10)
1 (2.00)
0 (0.00)
2 (10.0)
C > A
G > A
A > G
A>C
A > G f
G > A f
A>C
G > A
A > G
A > G f
A > G
C>G
A > G f
A > G
T> A
A > G f
A > G f
G> A f
A = 40.7
A = 36.4
G = 33.3
C = 5.60
G = 8.60
A = 23.2
C = 8.50
A = 1 8.8
188 (35.0) 258 (48.0) 89(17.0) 0.874
216(40.4) 248(46.4) 71(13.2) 0.419
243(45.4) 228(42.6) 64(12.0) 0.491
477(89.1) 56(10.5) 2(0.40) 1.000
448 (83.7) 82 (15.3) 5(1.00) 0.690
323 (60.4) 176(32.9) 36(6.70) 0.291
449 (83.9) 81 (15.1) 5 (1.00)
G = 1 1 .0 423(79.1) 106(19.8) 6(1.10)
G = 1 8.6
G = 2.60
G = 48.0
G = 12.3
G = 9.10
A = 20.9
G = 13.7
G = 1 7.9
0.812
355 (66.4) 159 (29.7) 21 (3.90) 0.782
0.050
358 (66.9) 155 (29.0) 22 (4.10) 1.000
508 (95.0) 26 (4.80) 1 (0.20) 1.000
144 (26.9) 268(50.1) 123 (23.0) 0.482
411 (76.8) 116 (21.7) 8 (1.50) 0.474
438(81.9) 97(18.1) 0(0.00)
0.001
335 (62.6) 1 76 (32.9) 24 (4.50) 0.262
399 (74.6) 1 25 (23.4) 1 1 (2.00)
367 (68.6) 145 (27.1) 23(4.30) 0.035
A = 27.5 271 (50.7) 234 (43.7) 30 (5.60) 0.522
Table 1 Functional consequence and prevalence of inflammatory-associated sequence variants (Continued)
rs4674257 ++
IL8RB
Near gene 5'
TFBS
G > A
A =
25.0
14 (58.3)
8 (33.3)
2 (8.30)
G > A
A =
20.1
347 (64.9)
161 (30.10)
27 (5.00)
0.468
rs4674259 +
IL8RB
UTR'5
TFBS
A > G
G =
23.9
12 (52.2)
1 1 (47.8)
0 (0.00)
A > G
G =
20.0
349 (65.0)
1 58 (30.0)
28 (5.00)
0.176
rs486907 +
RNASEL
Exon 1
nsSNP,
benign
G > A
A =
16.7
1 6 (66.7)
8 (33.3)
0 (0.00)
G > A
A =
13.2
402 (75.1)
1 25 (23.4)
8 (1.50)
0.528
rs6726713 + *
IL1R2
Near gene 5'
TFBS
C>T
T=
11.2
38 (77.6)
11 (22.4)
0 (0.00)
G>A +
A =
12.1
417 (78.0)
106 (19.8)
12 (2.20)
0.689
rs673*
TNF
Near gene 5'
TFBS
G > A
A =
13.7
45 (72.6)
1 7 (27.4)
0 (0.00)
G > A
A =
17.4
364 (68.0)
156 (29.2)
15 (2.80)
0.546
rs8 178433*
IL10RB
Near gene 5'
TFBS
T> G
G =
12.9
46 (74.2)
1 6 (25.8)
0 (0.00)
A>C t
C =
12.4
408 (76.3)
121 (22.6)
6 (1.10)
0.811
rs949963*
IL1R1
Near gene 5'
TFBS
G > A
A =
31.1
31 (50.8)
22 (36.1)
8 (13.1)
G > A
A =
33.1
249 (46.5)
218 (40.8)
68 (12.7)
0.771
rs9610 +
IL10RA
UTR'3
miRNA
A > G
G =
41.9
20 (32.3)
32 (51.6)
10 (16.1)
A > G
G =
33.9
237 (44.3)
233 (43.5)
65 (12.2)
0.184
rs999788*
IL10RB
Near gene 5'
TFBS
C>T
T=
19.5
40 (67.8)
1 5 (25.4)
4 (6.80)
G>A +
A =
12.4
410 (76.6)
117 (21.9)
8 (1.50)
0.026
+ The nucleotide change may vary relative to that reported in NCBI depending on whether the genotyping was performed using the sense or anti-sense DNA strand.
+t The chi-square test was used to assess differences in the overall genotype frequencies comparing men of African Descent as reported in NCBI to those in the total population from the current study. P-values generated from
the Fisher's exact test (in italics) were used when expected genotype counts were < 5 for either cases or controls.
Abbreviations: MAF Minor Allele Frequency; UTR untranslated region; TFBS transcription factor binding site; nsSNP non-synonymous coding SNP; miRNA microRNA binding site; NCBI National Center for Biotechnology
Information Entrez SNP.
*NCBI AFR1 or African American Population Panel.
**NCBI ASW Population Panel.
Jones et al. Hereditary Cancer in Clinical Practice 201 3, 11:19 Page 7 of 1 1
http://www.hccpjournal.eom/content/1 1/1/19
Table 2 Relationship between inflammatory related sequence variants and prostate cancer risk among men of
African Descent
Genes
dbSNP ID location
predicted function
Genotype
Cases
n (%)
Controls
n (%)
Unadjusted
OR (95%CI) t
Adjusted
OR (95%CI) +
p-value*
p trend
Bonferroni
correction
IL1R2
rsl 1886877
GG
87 (31.2)
211 (39.4)
1 .00 (referent)
1 .00 (referent)
0.034
0.010
NS
Intron 1
GA
149 (53.4)
265 (49.5)
1 .36 (0.99, 1 .88)
1.35 (0.92,1.98)
0.058
AA
43 (1 5.4)
59 (11.1)
1.77 (1.11, 2.82)
1.92 (1.11, 3.32)
0.017
GA + AA
1 92 (68.8)
324 (60.6)
1.44 (1.06, 1.95)
1.46 (1.01, 2.10)
0.021
AA vs (GG + GA)
1 .47 (0.96,2.24)
1.61 (0.98,2.63)
0.074
ILIA
rs17561
CC
1 95 (69.9)
358 (66.9)
1 .00 (referent)
1 .00 (referent)
0.025
0.108
NS
Exon 4
CA
82 (29.4)
1 55 (29.0)
0.97 (0.70,1.34)
1.01 (0.68,1.48)
0.858
Splicing
AA
2 (0.70)
22 (4.10)
0.17 (0.04, 0.72)
0.40 (0.08,1.83)
0.016
nsSNP
GA + AA
84 (30.1)
177 (33.1)
0.87 (0.64,1.20)
0.96 (0.66,1.40)
0.388
benign
AA vs (CC + CA)
0.17 (0.04, 0.72)
0.40 (0.09,1.82)
0.016
IL8RB
rs 11574752
GG
230 (82.4)
435 (81.3)
1 .00 (referent)
1 .00 (referent)
0.011
0.784
NS
3'-UTR
GA
43 (1 5.4)
99 (18.5)
0.82 (0.55,1.21)
0.90 (0.56,1.40)
0.326
miRNA
AA
6 (2.20)
1 (0.20)
11.3 (1.36, 94.6)
38.4 (3.86, 382.8)
0.009
GA + AA
49 (17.6)
100 (18.7)
0.93 (0.64,1.35)
1.08 (0.69,1.70)
0.693
AA vs (GG + GA)
11.7 (1.40, 98.0)
39.2 (3.94, 390)
0.008
TNF
rs 1800629
GG
171 (61.2)
368 (68.8)
1 .00 (referent)
1 .00 (referent)
0.047
0.087
NS
5' near gene
GA
1 03 (37.0)
1 53 (28.6)
1.45 (1.06, 1.97)
1 .54 (1 .06, 2.24)
0.019
TFBS
AA
5 (1 .80)
14 (2.60)
0.77 (0.27, 2.16)
1 .30 (0.37,4.60)
0.619
GA + AA
108 (38.8)
167 (31.2)
1.39 (1.03, 1.90)
1.53 (1.06, 2.20)
0.032
AA vs (GG + GA)
0.68 (0.24,1.91)
1.13 (0.32,3.90)
0.462
TNF
rs673
GG
171 (61.3)
364 (68.0)
1 .00 (referent)
1 .00 (referent)
0.009
0.228
NS
5' near gene
GA
106 (38.0)
156 (29.2)
1.45 (1.06, 2.00)
1.50 (1.04, 2.16)
0.018
TFBS
AA
2 (0.70)
1 5 (2.80)
0.28 (0.06, 1 .26)
0.47 (0.09,2.40)
0.097
GA + AA
108 (39.1)
171 (32.0)
1 .34 (0.99, 1 .82)
1.43 (1.00, 2.05)
0.055
AA vs (GG + AG)
0.25 (0.06,1.10)
0.41 (0.08,2.07)
0.067
ILIA
rs2856836
AA
196 (70.3)
358 (66.9)
1 .00 (referent)
1 .00 (referent)
0.024
0.089
NS
3'-UTR
AG
81 (29.0)
1 55 (29.0)
0.96 (0.69,1.32)
0.99 (0.67,1.45)
0.776
miRNA
GG
2 (0.70)
22 (4.10)
0.17 (0.04, 0.71)
0.40 (0.09,1.82)
0.016
AG + GG
83 (29.7)
177 (33.1)
0.86 (0.63,1.17)
0.94 (0.65,1.36)
0.333
GG vs (AA + AG)
0.17 (0.04, 0.72)
0.40 (0.09,1.82)
0.016
IL10RA
rs4252243
GG
1 34 (48.4)
268 (50.4)
1 .00 (referent)
1 .00 (referent)
0.066
0.168
NS
5' near gene
GA
115 (41.5)
234 (44.0)
0.98 (0.72,1.32)
0.83 (0.58,1.18)
0.893
TFBS
AA
28 (10.1)
30 (5.60)
1.86 (1.07, 3.24)
1.62 (0.82, 3.21)
0.028
GA + AA
143 (51.6)
264 (49.6)
1.08 (0.81,1.44)
0.91 (0.64,1.28)
0.605
AA vs (GG + GA)
1.88 (1.10, 3.21)
1.77 (0.91, 3.43)
0.021
+ On a separate line before the text regarding the chi-square test p-values state the following:
f Boldface odd ratios (ORs) and 95% confidence interval (CI) indicate a significant relationship between the selected SNPs and prostate cancer risk.
From top to bottom within the column, the chi-square test p-values were used to determine the difference in the genotype frequencies between cases and
controls for the overall, minor/major versus major/major genotypes, as well as the dominant (i.e., minor/minor versus major/major), co-dominant (minor/minor +
major/minor versus major/major), and recessive genetic models (minor/minor versus major/major + major/minor). P-values generated from the Fisher's Exact test
(in italics) were calculated when expected genotype counts were < 5 for either cases or controls. Statistically significant p-values are marked in bold face.
Abbreviations: (777?, untranslated region; TFBS, transcription factor binding site; miRNA, microRNA binding site; NS, non-significant.
Table 3 Relationship between inflammatory related sequence variants and prostate cancer risk among U.S. and Jamaican men
Genes
dbSNP ID location
predicted function
Genotype
Unadjusted OR
(95%CI) US ment
Age-adjusted OR
(95%CI) US ment
Unadjusted OR
(95%CI) Jamaican ment
Age-adjusted OR
(95%CI) Jamaican ment
p-value
US men*
p-value
Jamaican men*
p-trend
US men
p-trenc
Jamaican
IL1B
rs1071676
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.050
0.550
0.022
0.2/6
UTR'3
GC
0.72 (0.48, 1.10)
0.70 (0.42, 1.14)
1.39 (0.71, 2.70)
1 .28 (0.62, 2.64)
0.124
0.338
miRNA
CC
0.16 (0.02, 1.25)
0.19 (0.02, 2.00)
2.02 (0.18, 22.8)
1.15 (0.10, 14.6)
0.035
0.500
GC + CC
0.66 (0.44, 1 .00)
0.66 (0.40, 1.10)
1 .42 (0.74, 2.72)
1 .26 (0.62, 2.60)
0.050
0.294
CC vs (GG + GC)
0.18 (0.02, 1.36)
0.21 (0.02, 2.18)
1.89 (0.16, 21.1)
1.10 (0.08, 13.7)
0.046
0.525
IL1B
rs1 143634
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.051
0.447
0.016
0.203
Exon 4
GA
0.67 (0.44, 1.01)
0.65 (0.40, 1 .06)
1.51 (0.76, 3.00)
1.37 (0.64, 2.90)
0.058
0.243
Splicing
AA
0.21 (0.02, 1.60)
0.24 (0.02, 2.86)
2.05 (0.18, 23.0)
1.16 (0.10, 14.6)
0.080
0.496
GA + AA
0.63 (0.42, 0.95)
0.62 (0.38, 1 .02)
1 .54 (0.78, 3.00)
1 .36 (0.65, 2.82)
0.028
0.208
cds-synonymous
AA vs (GG + GA)
0.23 (0.02, 1 .80)
0.27 (0.02, 3.20)
1.89 (0.16, 21.1)
1.10 (0.08, 13.7)
0.105
0.525
IL1R2
rs 11886877
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.007
0.889
0.002
0.631
ntron 1
GA
1.60 (1.08, 2.40)
1.63 (1.00, 2.64)
0.92 (0.50, 1 .68)
0.94 (0.48, 1 .80)
0.020
0.782
AA
2.34 (1.31, 4.16)
2.75 (1.38, 5.50)
0.82 (0.36, 1 .86)
0.94 (0.38, 2.30)
0.004
0.633
GA + AA
1.72 (1.18, 2.52)
1.82 (1.14, 2.88)
0.89 (0.50, 1 .58)
0.94 (0.50, 1 .74)
0.005
0.700
AA vs (GG + GA)
1.76 (1.04, 2.96)
2.05 (1.10, 3.80)
0.86 (0.40, 1 .80)
0.97 (0.43, 2.20)
0.033
0.691
RNASEL
rsl 21 35247
AA
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.800
0.025
0.909
0.216
UTR'3
AG
1 .06 (0.72, 1 .58)
1.14 (0.71, 1.84)
2.17 (1.14,4.12)
2.10 (1.04, 4.24)
0.756
0.018
TFBS
GG
0.77 (0.30, 1 .96)
0.70 (0.24, 2.10)
0.45 (0.08, 2.40)
0.28 (0.04, 1 .70)
0.570
0.284
miRNA
AG + GG
1 .02 (0.70, 1 .50)
1 .07 (0.68, 1 .68)
1.81 (0.99, 3.30)
1 .68 (0.88, 3.24)
0.906
0.053
GG vs (AG + AA)
0.76 (0.30, 1.92)
0.67 (0.22, 1 .97)
0.36 (0.06, 1.91)
0.22 (0.04, 1 .35)
0.555
0.196
TNF
rsl 800629
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.101
0.782
0.113
0.549
5' near gene
GA
1.50 (1.03, 2.20)
1 .52 (0.96, 2.42)
1.21 (0.68, 2.12)
1.41 (0.78, 2.63)
0.034
0.518
TFBS
AA
0.90 (0.28, 2.80)
1.51 (0.36, 6.24)
1.00 (0.06, 16.3)
1 .00 (0.06, 1 7.2)
0.551
0.752
GA + AA
1.44 (0.99, 2.10)
1 .53 (0.97, 2.40)
1.20 (0.68, 2.10)
1 .40 (0.75, 2.60)
0.050
0.525
AA vs (GG + GA)
0.78 (0.25, 2.42)
1 .32 (0.32, 5.40)
0.94 (0.06, 1 5.2)
0.88 (0.05, 15.0)
0.452
0.734
ILIA
rsl 800587
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.088
0.450
0.028
0.224
UTR'5
GA
0.75 (0.50, 1.10)
0.68 (0.42, 1 .08)
1 .38 (0.76, 2.50)
1 .42 (0.74, 2.72)
0.144
0.297
TFBS
AA
0.56 (0.32, 0.96)
0.78 (0.40, 1 .53)
1 .56 (0.69, 3.50)
1 .64 (0.70, 4.00)
0.038
0.279
Splicing (ESE or
GA + AA
0.70 (0.48, 1 .00)
0.70 (0.45, 1.10)
1 .42 (0.80, 2.50)
1 .47 (0.80, 2.72)
0.053
0.222
ESS)
AA vs (GG + GA)
0.66 (0.40, 1.10)
0.96 (0.52, 1 .80)
1 .30 (0.62, 2.70)
1 .34 (0.60, 3.00)
0.105
0.478
MORA
rs4252243
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.062
0.620
0.275
0.329
Table 3 Relationship between inflammatory related sequence variants and prostate cancer risk among U.S. and Jamaican men (Continued)
5' near gene
GA
0.92 (0.63, 1.33)
0.70 (0.44, 1.10)
1 .24 (0.70, 2.20)
1.21 (0.64, 2.28)
0.648
0.448
TFBS
AA
2.02 (1 .04, 3.95)
2.10 (0.90, 4.98)
1 .50 (0.54, 4.26)
1 .04 (0.34, 3.20)
0.038
0.436
GA + AA
1.03 (0.72, 1.50)
0.81 (0.52, 1.30)
1.28 (0.74, 2.21)
1.15 (0.64, 2.10)
0.863
0.328
AA vs (GG + GA)
2.11 (1.10, 4.02)
2.49 (1.08, 5.72)
1.37 (0.50, 3.74)
1 .02 (0.40, 2.98)
0.023
0.539
TNF rs673
GG
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
1 .00 (referent)
0.027
0.452
0.279 0.874
5' near gene
GA
1.50 (1.02, 2.20)
1 .46 (0.92, 2.30)
1.22 (0.70, 2.14)
1.41 (0.76, 2.62)
0.025
0.498
TFBS
AA
0.24 (0.03, 1 .84)
0.54 (0.06, 4.44)
0.33 (0.03, 3.24)
0.40 (0.03, 4.70)
0.116
0.315
GA + AA
1 .38 (0.95, 2.00)
1 .40 (0.88, 2.20)
1.14 (0.66, 2.00)
1 .33 (0.72, 2.46)
0.087
0.635
AA vs (GG + GA)
0.21 (0.02, 1.60)
0.47 (0.06, 3.91)
0.31 (0.03, 2.98)
0.35 (0.03, 4.08)
0.080
0.286
On a separate line before the text regarding the chi-square test p-values state the following:
tBoldface odd ratios (ORs) and 95% confidence interval (CI) indicate a significant relationship between the selected SNPs and prostate cancer risk.
*From top to bottom within the column, the chi-square test p-values were used to determine the difference in the genotype frequencies between cases and controls for the overall, minor/major versus major/major ge-
notypes, as well as the dominant (i.e., minor/minor versus major/major), co-dominant (minor/minor + major/minor versus major/major), and recessive genetic models (minor/minor versus major/major + major/minor).
P-values generated from the Fisher's Exact test (in italics) were calculated when expected genotype counts were < 5 for either cases or controls. Statistically significant p-values are marked in bold face.
Abbreviations: UTR, untranslated region; TFBS, transcription factor binding site; cds-syn, synonymous SNP; miRNA, microRNA binding site.
Jones et al. Hereditary Cancer in Clinical Practice 2013, 11:19
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Page 1 0 of 1 1
mesenchymal transition (EMT), by binding to IL1R2 to
increase prostate cancer tumorigenesis [30].
Out of 44 inflammatory-related sequence variants, 7
SNPs included in our study were evaluated in relation
to prostate cancer outcomes within 4 independent observa-
tional studies [6,7,10,11]. Commensurate with our findings,
two observational studies demonstrated that sequence
variants detected in IL10 (rsl800871, rsl800872) and IL8
rs4073 were not significantly related to prostate cancer risk
[6,11]. Inheritance of the TNF rsl800629 AA genotype was
associated with a significant 1.8 fold increase in prostate
cancer risk among Caucasian men in a small study (150
cases, 150 controls); however, this marker resulted in null
findings in a larger study (468 cases, 468 controls) [6,7]. In
our preliminary analyses, inheritance of one or more TNF
rsl800629 A alleles was marginally associated with a
1.5-fold increase in prostate risk; however, this relation-
ship did not survive adjustment after multiple hypothesis
testing. Lastly, IL10 rsl800896 G and IL1B rsl 143627 C
alleles had protective effects in two separate Caucasian sub-
populations. However, neither of these markers were signifi-
cantly related to prostate cancer among African- American
men in the current study. Casey and colleagues (2002)
showed a 2-fold increase in prostate cancer susceptibility
linked to inheritance of the RNASEL rs486907 AA geno-
type among mostly men of European descent [10]. This
locus was not related to prostate cancer risk among
African- Americans in the current study. Racial/ethnic dis-
parities in the aforementioned risk estimates may be attrib-
uted to differences in minor allele frequencies, failure to
adjust findings for multiple hypothesis testing or inadequate
sample size among men with African ancestry.
In this study, we considered the strengths, limitations
and future directions of the project. Forty-four sequence
variants were evaluated in relation to prostate cancer risk
among men of African Descent from the U.S. and Jamaica.
Upon stratification by study center, the IL1R2 rsl 1886877
locus was marginally related to prostate cancer among
men of African descent from the U.S. However, overall the
inflammatory-related sequence variants were not robustly
related to prostate cancer among our study participants.
Despite this, we cannot eliminate the possibility that IL1R2
and other inflammatory-related sequence variants not
included in this study may influence the risk of prostate
cancer development or aggressive tumor behavior. In
larger studies, the impact of individual or interaction
among inflammatory cytokine-associated sequence vari-
ants in relation to prostate cancer tumor grade, biochem-
ical or disease recurrence, and mortality using targeted
sequencing, in vitro studies, in silico and bioinformatics
tools. Such efforts will help to identify genetic markers
linked to disproportionately high prostate cancer
incidence, mortality, and morbidity rates among men of
African Descent. Population admixture, which commonly
occurs among men of African descent, may bias risk esti-
mates. However, adjustment of risk estimates by West
African Ancestry and/or age did not significantly modify
the directionality of observed risk estimates among men
from the U.S. (data not shown). Although, the sample
size of this study population is small, there was ample
statistical power to accurately detect risk estimates,
ranging between 1.4-1.8 or 0.55-0.70. Our findings are
important to genetic epidemiology research teams inter-
ested in pooling genetic and tumor characteristic data to
determine whether other variant inflammatory-related
cytokines contribute to prostate cancer susceptibility and
disease prognosis. Although this study displays a modest
association between inflammatory-related cytokine variant
IL1R2 rsl 1886877 and prostate cancer risk, this relation-
ship has yet to be tested biologically. The association of
IL1R2 rsl 1886877 with prostate cancer risk may prove to
be strong in a larger study population.
Conclusions
Chronic inflammation is an established risk factor of
prostate cancer and many studies argue that it can lead
to prostate cancer development. In this study, 44
inflammatory-related cytokine variants that may play a
role in chronic inflammation were analyzed in relation
to prostate cancer risk. Our preliminary data suggests that
the possession of IL1R2 rsl 1886877 locus modifies prostate
cancer susceptibility among individuals with African ances-
try in the U.S. However, the association of the IL1R2 variant
with prostate risk did not remain significant after adjust for
multiple hypothesis testing. Future studies with ample stat-
istical power to accommodate adjustment for multiple
comparisons bias, will enable us to evaluate the impact
of the IL1R2 variant or a combination of inflammatory
cytokine SNPs in relation to prostate cancer risk, tumor
grade, biochemical or disease recurrence, and mortality.
These studies will lead to the identification of genetic
markers that modify the susceptibility of individuals.
Abbreviations
SNP: Single nucleotide polymorphism; LR: Logistic regression.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
LRK and KSK: conceptualized the project. LRK, KSK, CR, MJ, NM, MT, SM:
participated in the study design. DZJ, LRK: composed the manuscript. DZJ,
LRK, CR, REF: revised subsequent manuscript drafts. DZJ, NCK: quality control
and statistical analysis. LRK: supervised quality control analysis, data-management
and statistical analysis. LRK, DZJ, CR, KSK: interpreted the data, gave
important intellectual input toward the introduction, results and/or
discussion. All co-authors: read and edited the manuscript drafts as well
as gave final approval of the final manuscript draft.
Acknowledgements
We thank Tiva T. VanCleave and Nicole A. Lavender for DNA sample
preparation. We appreciate the contract services of Expression Analysis, Inc.
(http://www.expressionanalysis.com) for the generation of genotype data.
Jones et al. Hereditary Cancer in Clinical Practice 2013, 11:19
http://www.hccpjournal.eom/content/1 1/1/19
Page 11 of 1 1
We offer gratitude to Dr. Rick Kittles for the donation of DNA samples from
prostate cancer patients.
Lastly, we value Peter Andrews for his service as a computer programming
consultant on this project.
Grant/Research support: Clinical Translational Science Pilot Grant to LRK; the
JGBCC Bucks for Brains "Our Highest Potential" in Cancer Research
Endowment to LRK; P20-MD0001 75 NIH NCMHD to KSK.
Author details
'Department of Pharmacology & Toxicology, University of Louisville,
Louisville, KY, USA. 2 Cancer Prevention and Control Program, Fox Chase
Cancer Center, Philadelphia, PA, USA. 3 Molecular and Cellular Biology
Program, State University of New York, Brooklyn, NY, USA. department of
Community Health and Psychiatry, University of West Indies, Mona, Kingston,
Jamaica, department of Basic Medical Sciences, University of the West
Indies, Mona Campus, Kingston, Jamaica, tropical Medicine Research
Institute, University of the West Indies, Mona, Kingston, Jamaica. 'Biomedical/
Biotechnology Research Institute (BBRI), North Carolina Central University,
Durham, NC, USA.
Received: 29 July 2013 Accepted: 3 December 2013
Published: 23 December 2013
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doi:1 0.1 1 86/1 897-4287-1 1-19
Cite this article as: Jones ef al: The impact of genetic variants in
inflammatory-related genes on prostate cancer risk among men of African
Descent: a case control study. Hereditary Cancer in Clinical Practice
2013 11:19.
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